d n c r e box egulatory information...these videos include music videos, clips from children’s...

DE NOVO CLASSIFICATION REQUEST FOR

EYEBOX

REGULATORY INFORMATION

FDA identifies this generic type of device as

Traumatic brain injury eye movement assessment aid A traumatic brain injury eye movement assessment aid is a prescription device that uses a patientrsquos tracked eye movements to provide an interpretation of the functional condition of the patientrsquos brain This device is an assessment aid that is not intended for standalone detection or diagnostic purposes

NEW REGULATION NUMBER 21 CFR 8821455

CLASSIFICATION Class II

PRODUCT CODE QEA

BACKGROUND

DEVICE NAME EyeBOX

SUBMISSION NUMBER DEN170091

DATE DE NOVO RECEIVED December 22 2017

CONTACT Oculogica Inc 33 Irving Place New York New York 10003

INDICATIONS FOR USE

The EyeBOX is intended to measure and analyze eye movements as an aid in the diagnosis of concussion within one week of head injury in patients 5 through 67 years of age in conjunction with a standard neurological assessment of concussion

A negative EyeBOX classification may correspond to eye movement that is consistent with a lack of concussion

A positive EyeBOX classification corresponds to eye movement that may be present in both patients with or without concussion

LIMITATIONS

For prescription use only

The EyeBOX device should not be used as a standalone assessment of concussion

The safety and effectiveness of the EyeBOX device has not been established in patients suspected of having moderate or severe TBI including patients with a Glasgow Coma Scale score less than 13 and patients with evidence of structural injury or intracranial hemorrhage as determined by imaging modalities

The safety and effectiveness of the EyeBOX device has not been established in patients who have incurred an injury more than 1 week before assessment with the EyeBOX

The safety and effectiveness of the EyeBOX device has not been established in patients who have any of the following

bull Have visual acuity worse than 2080 bull Have a history of disordered eye movement (including strabismus diplopia and

amblyopia) bull Have conditions that affect the eye tissue including retinal degeneration

cataracts and corneal scarring bull Have abnormal function of cranial nerves III IV or IV bull Are intoxicated or are under the influence of medication drugs or alcohol bull Have attention deficit hyperactivity disorder

The EyeBOX should only be used by physicians or under the direction of physicians who have been trained to use the device

The device should not be used as a substitute for a CT scan or as a stand-alone diagnostic device

REFER TO THE LABELING FOR A COMPLETE LIST OF WARNINGS PRECAUTIONS AND CONTRAINDICATIONS

DEVICE DESCRIPTION

The Oculogica EyeBOX system consists of an integrated stand eye-tracking camera video stimulus display screen and computer programmed for analysis of eye movements It is intended to detect abnormal eye movement that may be related to a concussion The device measures gaze calculates a score on a 0-20 scale based on these measurements and displays an EyeBOX classification based upon whether the scale value is above 10 or not Scale values of 10 or more yield a positive EyeBOX classification while scale values under 10 yield a negative EyeBOX classification

De Novo Summary (DEN170091) Page 2 of 14

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1] Cabull

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-He11lt1est

IIMbulldegbt ouHon middot-- fivcor MTII --

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Figure 1 Oculogica EyeBOX device

Eye-tracking camera The device eye-tracking camera detects eye motion events and computes the gaze coordinates for each eye over a period of 220 seconds The camera is a commercially available system that uses an infrared illumination technique to capture 500 frames of gaze data per second for each eye to track the movement of the pupil Patient-specific calibration is not used for tracking of pupillary movement

Stimulus screen The stimulus screen is used to display a video that lasts 220 seconds The video is one of several pre-determined videos that may be selected These videos include music videos clips from childrenrsquos movies sports clips talent performances and other television clips The video aperture is square approximately one ninth the size of the LCD screen one third each area dimension resulting in one ninth total stimulus screen area The trajectory around the Stimulus Screen follows a predefined discrete path of 5 cycles along the perimeter of the stimulus screen

Software analysis During eye tracking EyeBOX collects 220 seconds of binocular gaze data at 500Hz as the patient watches the video stimulus go around the screen five times The first and last ten seconds of data are discarded The data are processed for blinks and normalized A score between 0 and 20 is the calculated from the normalized data Scores of 10 or more are presented as consistent with the possible presence of concussion


Ocul09ica r-a middot--- -

EyeBOX Report FM+middot I 0CcJampOoM Oiecalll ampROOII

__ v~ lteletfft~ 9Mbull9h

8())( - lt 100 M0llllilll l10bHqi 006 -~Mot - - - _ - Ollll~bullbull -middot- 0~1bull1 ~ -- --- Hf~ r

__ 1tftl201t

_ --- JMUU1

LT

L1bullS

D d omiddot L1 0

u bullbull 0

bullbull YOI~

0 0 - -LS bullbull _

0 17 LJ 7~~

_10 -100010001J

Figure 2 below shows a sample clinical report for a normal patient The five plot pairs on the left-hand side (L1 through R5) are the left and right eye tracking for each of the five cycles as the eyes follow the aperture around the monitor The two plots at the top right (L1-5 and R1-5) are all five cycles for the left and right eye superimposed The two boxes below that (L Avg and R Avg) are the averages of five cycles The three line plots on the lower right are the differences in the x direction for the left and right eye the differences in the y direction for the left and right eye and an overlay plot of the individual left and right x and y plots on the same timeline

Figure 2 EyeBOX clinical report


SUMMARY OF NONCLINICALBENCH STUDIES

BIOCOMPATIBILITYMATERIALS

The device does not have patient-contacting materials because the device is intended for use with biocompatible drapes for the patient chinrest and headrest Therefore a full biocompatibility evaluation according to ISO 10993-1 was not needed in accordance with the FDA 2016 Guidance Document Use of International Standard ISO 10993-1 Biological evaluation of medical devices - Part 1 Evaluation and testing within a risk management process

STERILITY

The device is provided non-sterile Cleaning instructions are provided in the user manual

ELECTROMAGNETIC CAPABILITY amp ELECTROMAGNETIC SAFETY

Performance testing was conducted to demonstrate conformance to the following standards

ANSIAAMI ES60601-1 2005 and A12012 Medical electrical equipment Part 1 General requirements for basic safety and essential performance

IEC 60601-1-22014 (4th edition) Medical electrical equipment ndash Part 1-2 General requirements for basic safety and essential performance ndash Collateral Standard Electromagnetic Compatibility ndash Requirements and Tests

Modifications were made to the device to conform to the requirements of EN 61000-4-22008 Electrostatic Discharge Immunity by adding a non-conductive coating to the

discharge Marketed versions of the device device power button to mitigate the risks of device shutdown after electrostatic

(b) (4)

SOFTWARE

A failure or latent flaw in the software for the EyeBOX could indirectly result in patient injury therefore the software of this device is considered to have a ldquoModeraterdquo level of concern The submission contained all the elements of software documentation corresponding to the ldquoModeraterdquo level of concern as outlined in the FDA guidance document ldquoGuidance for the Content of Premarket Submissions for Software Contained in Medical Devicesrdquo Adequate documentation describing the software firmware software specifications architecture design software development environment traceability revision level history and unresolved anomalies provide the foundation for the conclusion that the software will operate in the manner described in the specifications Hazard analysis characterized software risks including device malfunction and measurement-related errors The submission describes verification and


validation testing to address the potential hazards with satisfactory results The analysis algorithm was provided describing how the data are collected how the data are pre-processed (including artifact removal and normalization) the underlying model that is applied to the processed data and how the final device output(s) are calculated from the processed data

PERFORMANCE TESTING - BENCH

Testing was performed to demonstrate conformance with the following standards

IEC 624712006 Photobiological Safety of Lamps and Lamp Systems

ISO 15004-22007 Ophthalmic Instruments - Fundamental Requirements and Test Methods Part 2 Light Hazard Protection

SUMMARY OF CLINICAL INFORMATION

Study overview

In the pivotal clinical study EyeBOX results were compared to a trial-specific clinical reference standard for concussion because there is no ldquogold standardrdquo method to diagnose concussion Initially a 3-clinician panel was the clinical reference standard Because 844 of the first N=199 adjudications had at least one clinician render a recommendation of ldquouncertainrdquo for the patientrsquos concussion status investigators became concerned that the resulting clinical reference standard would not be interpretable At this point in the study they revised the clinical reference standard Using the revised standard a subject had a concussion if they exhibited (a) alteration of consciousness (AOC) or altered mental status (AMS) and scored less than 23 on the SCAT 3 Standardized Assessment of Concussion (SAC) and greater than 25 on the SCAT3 Symptom Severity Score (SSS) or (b) if they did not exhibit AOCAMS but scored SAClt15 and SSSgt32 on the SCAT 3 The presence of AOCAMS was based on any of the following self-report witness report or the following responses to the SCAT3 SSS ldquoDifficulty Rememberingrdquo ge 4 or ldquoConfusionrdquo ge 4 or Child-SCAT3 ldquoI get confusedrdquo ge 2 or ldquoI forget thingsrdquo ge 2 The results of the device output remained blinded for analysis when the reference standard was changed and remained blinded until the final study analysis

N=293 subjects who were screened met the study inclusion criteria Of these subjects 10 were excluded from analysis because the user did not save the eye-tracking scan and one subject was excluded because of missing concussion symptom question responses There are complete data for analysis from 282 enrolled subjects assessed with the device within 2 weeks of injury however 263 of the 282 subjects were assessed with the device within 1 week of injury yielding insufficient evidence of device effectiveness beyond 1 week after injury

Inclusion criteria 1 Ages 4 through 67 years (inclusive) 2 Diagnosis of traumatic brain injury with a potential for concussion


3 Baseline vision correctable to within 20500 bilaterally 4 No prior history of diagnosed ocular motility disorder 5 Able to provide a complete ophthalmologic medical and neurologic history and to list any

medications non-prescribed drugs or alcohol consumed within the 24 hours prior to tracking

Exclusion criteria 1 Penetrating head trauma 2 CT scan determined by the attending radiologist to demonstrate evidence of acute brain

injury including subdural epidural or intraparenchymal hemorrhage edema or mass effect 3 Burns anoxic injury multiple injuries or extensive injuries resulting in medical surgical or

hemodynamic instability 4 Prior history of ocular motility dysfunction 5 Prior extensive eye surgery 6 Physical or mental injury or baseline disability rendering task completion difficult 7 Intoxicated or have blood alcohol level greater than 02

Co-primary effectiveness endpoint The primary endpoint of the study is the sensitivity and specificity of the device in discriminating the presence or absence of concussion in head-injured patients per the eligibility criteria above A lower one-sided 95 confidence limit greater than 70 for sensitivity and a lower one-sided 95 confidence limit greater than 70 for specificity were defined as the pre-specified performance goals These goals were not met in the pivotal clinical study To supplement the primary analysis post-hoc analyses of positive predictive value (PPV) and negative predictive value (NPV) were conducted without defined performance goals Although the primary endpoint was not met the effectiveness analyses described above demonstrated that the probable benefit of the device outweighs the probable risk as discussed in the Benefit-Risk Determination section below

Results No adverse events (device-related or unrelated) were reported in the study

Of the 282 subjects included in the study analysis 46 met the revised clinical reference standard definition of concussion The EyeBOX identified 37 of these as positive for concussion (score 10 or higher) resulting in a measured sensitivity of 804 (661 919) This corresponds to a False Negative Rate (FNR) of 196 (946) Of the 236 subjects who did not meet the clinical reference standard definition of concussion EyeBOX identified 156 as negative for concussion (score less than 10) resulting in a measured specificity of 661 (597 721)

EyeBOX Clinical Classification Total Classification Concussion No Concussion

Positive 37 80 117 Negative 9 156 165

Total 46 236 282 Table 1 Classification results of the EyeBOX device versus Clinical Classification


The negative predictive value (NPV) of the device was 945 (899 975) The positive predictive value (PPV) was 31 6 (23 3 40 9) For PPV and NPV reference the study prevalence of clinical classification of concussion was 163 (46282) Observed device perfo1mance in pediatric patients was comparable to the observed perfo1mance in adults A sumrna1y of the device perfo1mance measures is provided in Table 2 below

All patients Adults

gt 21 years old Pediatrics

21 years old

Patients 282 (b) (4)

Concussions 46

Prevalence 163

Sensitivity (95 CI)

804 (661 -l(D) (4J

661 597 - 72 l )

Specificity (95 CI)

PPV (95 CI)

316 233 - 409)

NPV (95 CI)

945 (899 - 975)

Table 2 Summary of clinical performance

Test-retest reliability The Bland-Altman analysis - a measure of test-retest reliability - for the device score from 0-20 (EyeBOX Score) is shown in the Figure 3 below along with Bland-Altman analysis plots for two critical components of the EyeBOX Score in Figure 4 The propo1iion of equivalent outcomes (ie both tests result in a EyeBOX score~ 10 or both tests results in a EyeBOX score lt 10) was 793 (95 CI 678-875)

Cronbachs Alpha of the EyeBOX score for n=63 subjects was 079 (95 CI 069-089) Cronbachs Alpha and the propo1iion of equivalent outcomes for the EyeBOX score are shown in Table 2 below

The Cronbach s Alpha of the critical components of the EyeBOX score for n=63 subjects was 069 (054 084) and 088 (083 094)

De Novo Summay (DENJ70091) Page 8 of 14

ltr 0 q 0

N 0

Q) q

u 0 C ~ Q)

t 0

0 0 q 0

N 0 0

9

00

o +1 96SD ~ ~ - - - - - - - - - - _ o - - - - - - - - - - 987 -0 rn O 0

-0

D

- -----------o-- 0 0 -- g- --- -19069~0

----------------- ------------------0 5 10 15

Mean BOX N=63

ltr 0 q 0

0

N

0

+1 96SO 0 ci _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 0020738 _

_ _ _ _ _ _ _ _ Q __ ~ __ +1 96SO

0002235

0 0 0 0

0 0 0 0 MEAN

o o O o -7 9e-05 ----o-~-o~-0------------ - ---- ~ ~ ~ ----------Q ------- o~i - ~ --- ~0 - ~-----------

0 0 0 deg 8 0

oo 0 0

0

0 0

------ - -- - --------------- - --- - - - - - - - - 0 - - 0 - -196 so

-0002394 ---------------- ~-----------0001 0002 0003 0004 0005 0006

Mean N=63

Q) u C ~ Q)

t 0

Group Proportion of Equivalent Outcomes

All Test-Retest Subjects (N=63)

95CI 79-3 (678 87-5)

0 q 0

N 0

9

MEAN JJ ____________________ -5 4e-05 _

e O 0

0

-196 so _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ -0020846 _

000 002 004 006

Mean N=63

Cron actis Alpha of BOX Score 95CI

079 (069 089

0

008 010

Figure 3 Bland-Altman analysis of EyeBOX score in N=63 patients

Figure 4 Bland-Altman analysis of critical component measurements of EyeBOX score in N=63 patients

Table 3 Proportion of equivalent outcomes and Cronbachrsquos Alpha of EyeBOX Score

Pediatric Extrapolation

Clinical data were collected in pediatric patients to support safe and effective use in pediatric patients age 5-21 The 95 confidence intervals for pediatric sensitivity specificity

(b) (4)


positive predictive value and negative predictive value overlapped with the corresponding adult performance values as shown in Table 2 above Extrapolation is not necessary

LABELING

User manual labeling was provided that

States that the device is not intended to represent a standalone diagnosis and other caveats for device use and interpretation of its results

States that not all patients with concussion will have eye tracking abnormalities Identifies the visual acuity levels for which the device is intended to be used Describes the clinical study performed with the device including a description of the

clinical reference standard and a description of the sensitivity specificity positive predictive value and negative predictive value reported in the clinical study

Describes the test-retest reliability of the device including Bland-Altman analysis plots Describes how the test administrator and user should interact with the device Includes a sample clinical report Describes the electromagnetic compatibility (EMC) environment for use

RISKS TO HEALTH

The table below identifies the risks to health that may be associated with use of the traumatic brain injury eye movement assessment aid and the measures necessary to mitigate these risks

Identified Risks to Health Mitigation Measures Incorrect or misinterpreted results including

False positive brain injury when in fact none is present

False negative no brain injury when in fact brain injury is present

Clinical performance testing Software verification validation and hazard analysis and Labeling

Interference with other devices Electromagnetic compatibility (EMC) testing and Software verification validation and hazard analysis

Electrical shock or burn Electrical safety testing and Software verification validation and hazard analysis

Adverse tissue reaction Biocompatibility evaluation Eye hazard or injury Light hazard assessment

SPECIAL CONTROLS

In combination with the general controls of the FDampC Act the traumatic brain injury eye movement assessment aid is subject to the following special controls

De Novo Summary (DEN170091) 0 of 14

(1) Clinical performance data under anticipated conditions of use must evaluate tracked eye movement in supporting the indications for use and include the following (i) Evaluation of sensitivity specificity positive predictive value and negative

predictive value using a reference method of diagnosis

(ii) Evaluation of device test-retest reliability and (iii) A description of the development of the reference method of diagnosis which may

include a normative database to include the following (A) A discussion of how the clinical work-up was completed to establish the

reference method of diagnosis including the establishment of inclusion and exclusion criteria and

(B) If using a normative database a description of how the ldquonormalrdquo population was established and the statistical methods and model assumptions used

(2) Software verification validation and hazard analysis must be performed Software documentation must include a description of the algorithms used to generate device output

(3) Performance testing must demonstrate the electrical safety and electromagnetic compatibility (EMC) of the device

(4) The patient-contacting components of the device must be demonstrated to be biocompatible

(5) A light hazard assessment must be performed for all eye-tracking and visual display light sources

(6) Labeling must include (i) A summary of clinical performance testing conducted with the device including

sensitivity specificity positive predictive value negative predictive value and test-retest reliability

(ii) A description of any normative database that includes the following (A) The clinical definition used to establish a ldquonormalrdquo population and the specific

selection criteria (B) The format for reporting normal values (C) Examples of screen displays and reports generated to provide the user results

and normative data (D) Statistical methods and model assumptions and (E) Any adjustments for age and gender

(iii) A warning that the device should only be used by trained healthcare professionals (iv) A warning that the device does not identify the presence or absence of traumatic

brain injury or other clinical diagnoses (v) A warning that the device is not a standalone diagnostic and (vi) Any instructions to convey to patients regarding the administration of the test and

collection of test data


BENEFIT-RISK DETERMINATION

The risks of the device are based on data collected in the clinical study described above

No device related serious or non-serious adverse events occmTed in the clinical study

The major risk of the EyeBOX device is a false negative result Clinical trial results suggest a false negative report from the device would be expected in approximately 20 of patients and could result in a patient with a tme concussion continuing activities that could result in fmther patient haims including an increased risk of persistent post-concussive symptoms or a second concussion Cumulative head injmy exposure may result in long-te1m brain damage The risk of a false negative repo1t is that a patient would develop a false sense of safety and continue activities with increased risk of cumulative head injuries

These risks are initigated by using this device as pait of a multimodal evaluation which includes histo1y of inild head injmy injmy details and the cmTent signs and symptoms on examination The EyeBOX results should not be used as the sole measure to diagnose or exclude concussion and is not intended to be used in patients with moderate or severe injmy

The probable benefits of the device aimiddote also based on data collected in the clinical study as described above

Compared to a reference standaimiddotd to evaluate for the presence or absence of concussion the device had a sensitivity of 804 (37 46) and a specificity of 661 (156236) In the population studied negative predictive value (NPV) was 945 (156165) and positive predictive value (PPV) was 316 (37 117) The false negative rate was 196 The benefit of an EyeBOX evaluation is an objective assessment of eye movements to supplement existing neurocognitive assessments as an aid in diagnosis of concussion This benefit is of sufficient magnitude to serve as an additional assessment to help dete1mine the presence of eye movement abno1malities that suggest brain injmy and may help identify higher risk subjects to provide education to the patient that has been shown to be of prognostic benefit An objective measure of brain injmy may benefit an individual patient by providing additional motivation to avoid future head injmy however a negative result should be interpreted by the clinician with caution and in the context of other concussion assessments because the consequences of a inissed diagnosis may include persistent symptoms and increased risk of additional and cumulative head injmy Devices that aid in the assessment of concussion may help reduce the number of head injuries by providing objective evidence of brain injmy that is othe1wise not appaimiddotent to the patient

Data for use in pediatric patients did not show erfonnance differences between the ~o ulations as summarized reviousl in Table 2-(6) (4)

Additional factors to be considered in dete1mining probable risks and benefits for the EyeBOX include

a The perfo1mance goals for the device were not met in the pivotal clinical study The device s use as an adjunct to established methods for evaluation of concussion and high


negative predictive value (limiting the number of false negative results) were deemed acceptable to mitigate the risks of using the device as an aid in the assessment of concussion

b Although positive results by the device that did not coincide with clinical signs or symptoms of neurological injury were considered false positives there is a large amount of uncertainty in the clinical adjudication of concussion as demonstrated in the study thus raising the question as to whether these outcomes were truly false positives This uncertainty in clinical adjudication may have similar implications for the reported false negative rate

c The test-retest reliability of the EyeBOX as shown in Table 2 and Figure 3 demonstrated some variability in the EyeBOX score output when tested twice in the same patient However the level of variability was determined to be adequately mitigated by (1) the devicersquos performance in the pivotal clinical study (2) labeling that described the test-retest reliability to the user and (3) comparable test-retest reliability to medical devices and products that are currently legally marketed for the assessment of head injury

d Few alternative quantitative methods exist for aiding in the assessment of incident concussion Quantitative methods that do not rely on patient-self reporting of symptoms could aid the clinician by providing a more objective assessment of the signs of concussion

Patient Perspectives

This submission did not include specific information on patient perspectives for this device

BenefitRisk Conclusion

In conclusion given the available information above for the following indications for use statement




The probable benefits outweigh the probable risks for the EyeBOX The device provides benefits and the risks can be mitigated using general controls and the identified special controls


CONCLUSION

The De Novo request for the EyeBOX is granted and the device is classified as follows

Product Code QEA Device Type Traumatic brain injury eye movement assessment aid Regulation Number 21 CFR 8821455 Class II


The EyeBOX device should not be used as a standalone assessment of concussion

The safety and effectiveness of the EyeBOX device has not been established in patients suspected of having moderate or severe TBI including patients with a Glasgow Coma Scale score less than 13 and patients with evidence of structural injury or intracranial hemorrhage as determined by imaging modalities

The safety and effectiveness of the EyeBOX device has not been established in patients who have incurred an injury more than 1 week before assessment with the EyeBOX

The safety and effectiveness of the EyeBOX device has not been established in patients who have any of the following

bull Have visual acuity worse than 2080 bull Have a history of disordered eye movement (including strabismus diplopia and

amblyopia) bull Have conditions that affect the eye tissue including retinal degeneration

cataracts and corneal scarring bull Have abnormal function of cranial nerves III IV or IV bull Are intoxicated or are under the influence of medication drugs or alcohol bull Have attention deficit hyperactivity disorder

The EyeBOX should only be used by physicians or under the direction of physicians who have been trained to use the device

The device should not be used as a substitute for a CT scan or as a stand-alone diagnostic device

REFER TO THE LABELING FOR A COMPLETE LIST OF WARNINGS PRECAUTIONS AND CONTRAINDICATIONS

DEVICE DESCRIPTION

The Oculogica EyeBOX system consists of an integrated stand eye-tracking camera video stimulus display screen and computer programmed for analysis of eye movements It is intended to detect abnormal eye movement that may be related to a concussion The device measures gaze calculates a score on a 0-20 scale based on these measurements and displays an EyeBOX classification based upon whether the scale value is above 10 or not Scale values of 10 or more yield a positive EyeBOX classification while scale values under 10 yield a negative EyeBOX classification

De Novo Summary (DEN170091) of 14

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1] Cabull

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__ 1tftl201t

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L1bullS

D d omiddot L1 0

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0 17 LJ 7~~

_10 -100010001J







STERILITY








(b) (4)

SOFTWARE









Study overview


















All patients Adults


21 years old


Concussions 46

Prevalence 163

Sensitivity (95 CI)

804 (661 -l(D) (4J

661 597 - 72 l )

Specificity (95 CI)

PPV (95 CI)

316 233 - 409)

NPV (95 CI)

945 (899 - 975)






ltr 0 q 0

N 0

Q) q

u 0 C ~ Q)

t 0

0 0 q 0

N 0 0

9

00

o +1 96SD ~ ~ - - - - - - - - - - _ o - - - - - - - - - - 987 -0 rn O 0

-0

D

- -----------o-- 0 0 -- g- --- -19069~0

----------------- ------------------0 5 10 15

Mean BOX N=63

ltr 0 q 0

0

N

0

+1 96SO 0 ci _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 0020738 _

_ _ _ _ _ _ _ _ Q __ ~ __ +1 96SO

0002235

0 0 0 0

0 0 0 0 MEAN

o o O o -7 9e-05 ----o-~-o~-0------------ - ---- ~ ~ ~ ----------Q ------- o~i - ~ --- ~0 - ~-----------

0 0 0 deg 8 0

oo 0 0

0

0 0

------ - -- - --------------- - --- - - - - - - - - 0 - - 0 - -196 so

-0002394 ---------------- ~-----------0001 0002 0003 0004 0005 0006

Mean N=63

Q) u C ~ Q)

t 0



95CI 79-3 (678 87-5)

0 q 0

N 0

9

MEAN JJ ____________________ -5 4e-05 _

e O 0

0

-196 so _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ -0020846 _

000 002 004 006

Mean N=63


079 (069 089

0

008 010






(b) (4)



LABELING






RISKS TO HEALTH









SPECIAL CONTROLS














































CONCLUSION




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1] Cabull

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-He11lt1est


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__ 1tftl201t

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LT

L1bullS

D d omiddot L1 0

u bullbull 0

bullbull YOI~


0 17 LJ 7~~

_10 -100010001J







STERILITY








(b) (4)

SOFTWARE









Study overview


















All patients Adults


21 years old


Concussions 46

Prevalence 163

Sensitivity (95 CI)

804 (661 -l(D) (4J

661 597 - 72 l )

Specificity (95 CI)

PPV (95 CI)

316 233 - 409)

NPV (95 CI)

945 (899 - 975)






ltr 0 q 0

N 0

Q) q

u 0 C ~ Q)

t 0

0 0 q 0

N 0 0

9

00

o +1 96SD ~ ~ - - - - - - - - - - _ o - - - - - - - - - - 987 -0 rn O 0

-0

D

- -----------o-- 0 0 -- g- --- -19069~0

----------------- ------------------0 5 10 15

Mean BOX N=63

ltr 0 q 0

0

N

0

+1 96SO 0 ci _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 0020738 _

_ _ _ _ _ _ _ _ Q __ ~ __ +1 96SO

0002235

0 0 0 0

0 0 0 0 MEAN

o o O o -7 9e-05 ----o-~-o~-0------------ - ---- ~ ~ ~ ----------Q ------- o~i - ~ --- ~0 - ~-----------

0 0 0 deg 8 0

oo 0 0

0

0 0

------ - -- - --------------- - --- - - - - - - - - 0 - - 0 - -196 so

-0002394 ---------------- ~-----------0001 0002 0003 0004 0005 0006

Mean N=63

Q) u C ~ Q)

t 0



95CI 79-3 (678 87-5)

0 q 0

N 0

9

MEAN JJ ____________________ -5 4e-05 _

e O 0

0

-196 so _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ -0020846 _

000 002 004 006

Mean N=63


079 (069 089

0

008 010






(b) (4)



LABELING






RISKS TO HEALTH









SPECIAL CONTROLS














































CONCLUSION








__ 1tftl201t

_ --- JMUU1

LT

L1bullS

D d omiddot L1 0

u bullbull 0

bullbull YOI~


0 17 LJ 7~~

_10 -100010001J







STERILITY








(b) (4)

SOFTWARE









Study overview


















All patients Adults


21 years old


Concussions 46

Prevalence 163

Sensitivity (95 CI)

804 (661 -l(D) (4J

661 597 - 72 l )

Specificity (95 CI)

PPV (95 CI)

316 233 - 409)

NPV (95 CI)

945 (899 - 975)






ltr 0 q 0

N 0

Q) q

u 0 C ~ Q)

t 0

0 0 q 0

N 0 0

9

00

o +1 96SD ~ ~ - - - - - - - - - - _ o - - - - - - - - - - 987 -0 rn O 0

-0

D

- -----------o-- 0 0 -- g- --- -19069~0

----------------- ------------------0 5 10 15

Mean BOX N=63

ltr 0 q 0

0

N

0

+1 96SO 0 ci _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 0020738 _

_ _ _ _ _ _ _ _ Q __ ~ __ +1 96SO

0002235

0 0 0 0

0 0 0 0 MEAN

o o O o -7 9e-05 ----o-~-o~-0------------ - ---- ~ ~ ~ ----------Q ------- o~i - ~ --- ~0 - ~-----------

0 0 0 deg 8 0

oo 0 0

0

0 0

------ - -- - --------------- - --- - - - - - - - - 0 - - 0 - -196 so

-0002394 ---------------- ~-----------0001 0002 0003 0004 0005 0006

Mean N=63

Q) u C ~ Q)

t 0



95CI 79-3 (678 87-5)

0 q 0

N 0

9

MEAN JJ ____________________ -5 4e-05 _

e O 0

0

-196 so _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ -0020846 _

000 002 004 006

Mean N=63


079 (069 089

0

008 010






(b) (4)



LABELING






RISKS TO HEALTH









SPECIAL CONTROLS














































CONCLUSION







STERILITY








(b) (4)

SOFTWARE









Study overview


















All patients Adults


21 years old


Concussions 46

Prevalence 163

Sensitivity (95 CI)

804 (661 -l(D) (4J

661 597 - 72 l )

Specificity (95 CI)

PPV (95 CI)

316 233 - 409)

NPV (95 CI)

945 (899 - 975)






ltr 0 q 0

N 0

Q) q

u 0 C ~ Q)

t 0

0 0 q 0

N 0 0

9

00

o +1 96SD ~ ~ - - - - - - - - - - _ o - - - - - - - - - - 987 -0 rn O 0

-0

D

- -----------o-- 0 0 -- g- --- -19069~0

----------------- ------------------0 5 10 15

Mean BOX N=63

ltr 0 q 0

0

N

0

+1 96SO 0 ci _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 0020738 _

_ _ _ _ _ _ _ _ Q __ ~ __ +1 96SO

0002235

0 0 0 0

0 0 0 0 MEAN

o o O o -7 9e-05 ----o-~-o~-0------------ - ---- ~ ~ ~ ----------Q ------- o~i - ~ --- ~0 - ~-----------

0 0 0 deg 8 0

oo 0 0

0

0 0

------ - -- - --------------- - --- - - - - - - - - 0 - - 0 - -196 so

-0002394 ---------------- ~-----------0001 0002 0003 0004 0005 0006

Mean N=63

Q) u C ~ Q)

t 0



95CI 79-3 (678 87-5)

0 q 0

N 0

9

MEAN JJ ____________________ -5 4e-05 _

e O 0

0

-196 so _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ -0020846 _

000 002 004 006

Mean N=63


079 (069 089

0

008 010






(b) (4)



LABELING






RISKS TO HEALTH









SPECIAL CONTROLS














































CONCLUSION










Study overview


















All patients Adults


21 years old


Concussions 46

Prevalence 163

Sensitivity (95 CI)

804 (661 -l(D) (4J

661 597 - 72 l )

Specificity (95 CI)

PPV (95 CI)

316 233 - 409)

NPV (95 CI)

945 (899 - 975)






ltr 0 q 0

N 0

Q) q

u 0 C ~ Q)

t 0

0 0 q 0

N 0 0

9

00

o +1 96SD ~ ~ - - - - - - - - - - _ o - - - - - - - - - - 987 -0 rn O 0

-0

D

- -----------o-- 0 0 -- g- --- -19069~0

----------------- ------------------0 5 10 15

Mean BOX N=63

ltr 0 q 0

0

N

0

+1 96SO 0 ci _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 0020738 _

_ _ _ _ _ _ _ _ Q __ ~ __ +1 96SO

0002235

0 0 0 0

0 0 0 0 MEAN

o o O o -7 9e-05 ----o-~-o~-0------------ - ---- ~ ~ ~ ----------Q ------- o~i - ~ --- ~0 - ~-----------

0 0 0 deg 8 0

oo 0 0

0

0 0

------ - -- - --------------- - --- - - - - - - - - 0 - - 0 - -196 so

-0002394 ---------------- ~-----------0001 0002 0003 0004 0005 0006

Mean N=63

Q) u C ~ Q)

t 0



95CI 79-3 (678 87-5)

0 q 0

N 0

9

MEAN JJ ____________________ -5 4e-05 _

e O 0

0

-196 so _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ -0020846 _

000 002 004 006

Mean N=63


079 (069 089

0

008 010






(b) (4)



LABELING






RISKS TO HEALTH









SPECIAL CONTROLS














































CONCLUSION

















All patients Adults


21 years old


Concussions 46

Prevalence 163

Sensitivity (95 CI)

804 (661 -l(D) (4J

661 597 - 72 l )

Specificity (95 CI)

PPV (95 CI)

316 233 - 409)

NPV (95 CI)

945 (899 - 975)






ltr 0 q 0

N 0

Q) q

u 0 C ~ Q)

t 0

0 0 q 0

N 0 0

9

00

o +1 96SD ~ ~ - - - - - - - - - - _ o - - - - - - - - - - 987 -0 rn O 0

-0

D

- -----------o-- 0 0 -- g- --- -19069~0

----------------- ------------------0 5 10 15

Mean BOX N=63

ltr 0 q 0

0

N

0

+1 96SO 0 ci _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 0020738 _

_ _ _ _ _ _ _ _ Q __ ~ __ +1 96SO

0002235

0 0 0 0

0 0 0 0 MEAN

o o O o -7 9e-05 ----o-~-o~-0------------ - ---- ~ ~ ~ ----------Q ------- o~i - ~ --- ~0 - ~-----------

0 0 0 deg 8 0

oo 0 0

0

0 0

------ - -- - --------------- - --- - - - - - - - - 0 - - 0 - -196 so

-0002394 ---------------- ~-----------0001 0002 0003 0004 0005 0006

Mean N=63

Q) u C ~ Q)

t 0



95CI 79-3 (678 87-5)

0 q 0

N 0

9

MEAN JJ ____________________ -5 4e-05 _

e O 0

0

-196 so _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ -0020846 _

000 002 004 006

Mean N=63


079 (069 089

0

008 010






(b) (4)



LABELING






RISKS TO HEALTH









SPECIAL CONTROLS














































CONCLUSION





All patients Adults


21 years old


Concussions 46

Prevalence 163

Sensitivity (95 CI)

804 (661 -l(D) (4J

661 597 - 72 l )

Specificity (95 CI)

PPV (95 CI)

316 233 - 409)

NPV (95 CI)

945 (899 - 975)





De Novo Summay (DENJ70091) of 14

ltr 0 q 0

N 0

Q) q

u 0 C ~ Q)

t 0

0 0 q 0

N 0 0

9

00

o +1 96SD ~ ~ - - - - - - - - - - _ o - - - - - - - - - - 987 -0 rn O 0

-0

D

- -----------o-- 0 0 -- g- --- -19069~0

----------------- ------------------0 5 10 15

Mean BOX N=63

ltr 0 q 0

0

N

0

+1 96SO 0 ci _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 0020738 _

_ _ _ _ _ _ _ _ Q __ ~ __ +1 96SO

0002235

0 0 0 0

0 0 0 0 MEAN

o o O o -7 9e-05 ----o-~-o~-0------------ - ---- ~ ~ ~ ----------Q ------- o~i - ~ --- ~0 - ~-----------

0 0 0 deg 8 0

oo 0 0

0

0 0

------ - -- - --------------- - --- - - - - - - - - 0 - - 0 - -196 so

-0002394 ---------------- ~-----------0001 0002 0003 0004 0005 0006

Mean N=63

Q) u C ~ Q)

t 0



95CI 79-3 (678 87-5)

0 q 0

N 0

9

MEAN JJ ____________________ -5 4e-05 _

e O 0

0

-196 so _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ -0020846 _

000 002 004 006

Mean N=63


079 (069 089

0

008 010






(b) (4)



LABELING






RISKS TO HEALTH









SPECIAL CONTROLS














































CONCLUSION




ltr 0 q 0

N 0

Q) q

u 0 C ~ Q)

t 0

0 0 q 0

N 0 0

9

00

o +1 96SD ~ ~ - - - - - - - - - - _ o - - - - - - - - - - 987 -0 rn O 0

-0

D

- -----------o-- 0 0 -- g- --- -19069~0

----------------- ------------------0 5 10 15

Mean BOX N=63

ltr 0 q 0

0

N

0

+1 96SO 0 ci _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 0020738 _

_ _ _ _ _ _ _ _ Q __ ~ __ +1 96SO

0002235

0 0 0 0

0 0 0 0 MEAN

o o O o -7 9e-05 ----o-~-o~-0------------ - ---- ~ ~ ~ ----------Q ------- o~i - ~ --- ~0 - ~-----------

0 0 0 deg 8 0

oo 0 0

0

0 0

------ - -- - --------------- - --- - - - - - - - - 0 - - 0 - -196 so

-0002394 ---------------- ~-----------0001 0002 0003 0004 0005 0006

Mean N=63

Q) u C ~ Q)

t 0



95CI 79-3 (678 87-5)

0 q 0

N 0

9

MEAN JJ ____________________ -5 4e-05 _

e O 0

0

-196 so _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ -0020846 _

000 002 004 006

Mean N=63


079 (069 089

0

008 010






(b) (4)



LABELING






RISKS TO HEALTH









SPECIAL CONTROLS














































CONCLUSION





LABELING






RISKS TO HEALTH









SPECIAL CONTROLS














































CONCLUSION















































CONCLUSION














De Novo Summay (DENJ70091) of 14














CONCLUSION

















CONCLUSION




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